The present invention relates to novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
Substituted imidazo[1,2-a]pyridines, useful in the treatment of peptic ulcer diseases, are known in the art, e.g. from EP-B-0033094 and U.S. Pat. No. 4,450,164 (Schering Corporation); from EP-B-0204285 and U.S. Pat. No. 4,725,601 (Fujisawa Pharmaceutical Co.); and from publications by J. J. Kaminski et al. in the Journal of Medical Chemistry (vol. 28, 876-892, 1985; vol. 30, 2031-2046, 1987; vol. 30, 2047-2051, 1987; vol. 32, 1686-1700, 1989; and vol. 34, 533-541, 1991).
For a review of the pharmacology of the gastric acid pump (the H+, K+-ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.
It has surprisingly been found that compounds of the Formula I 
or a pharmaceutically acceptable salt thereof, are particularly effective as inhibitors of the gastrointestinal H+, K+-ATPase and thereby as inhibitors of gastric acid secretion.
In one aspect, the invention thus relates to compounds of the general Formula I 
or a pharmaceutically acceptable salt thereof, wherein
R1 is
(a) H,
(b) CH3, or
(c) CH2OH;
R2 is C1-C6 alkyl;
R3 is C1-C6 alkyl;
R4 is
(a) H, or
(b) halogen;
R5 is
(a) H, or
(b) C1-C6 alkyl;
R6 is
(a) H,
(b) C1-C6 alkyl carbonyl
(c) C3-C7 cycloalkyl carbonyl, in which the cycloalkyl group is optionally substituted by one or more substituents selected from, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94COOH or xe2x80x94COOxe2x80x94(C1-C6)alkyl
(d) Aryl C1-C6 alkyl carbonyl, in which aryl represents phenyl, pyridyl, thienyl or furanyl, optionally substituted by one or more substituents selected from, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94COOH or xe2x80x94COOxe2x80x94(C1-C6)alkyl
(e) C1-C6 alkoxy C1-C6 alkyl carbonyl
(f) C1-C6 alkoxy carbonyl
(g) aryl carbonyl, in which aryl represents phenyl, pyridyl, thienyl or furanyl, optionally substituted by one or more substituents selected from, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94COOH or xe2x80x94COOxe2x80x94(C1-C6)alkyl
(h) C3-C7 cycloalkyl C1-C6 alkylcarbonyl, in which the cycloalkyl group is optionally substituted by one or more substituents selected from, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94COOH or xe2x80x94COOxe2x80x94(C1-C6)alkyl
(i) C1-C6 alkoxy C1-C6 alkoxycarbonyl
(j) C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkylcarbonyl
(k) acarbamoylgroup with the formula 
xe2x80x83wherein R7 and R8 are the same or different and are H, or C1-C6 alkyl
(l) R9xe2x80x94(C1-C6)alkylcarbonyl
wherein R9 is
HOCxe2x95x90Oxe2x80x94, C1-C6 alkyl-Oxe2x80x94Cxe2x95x90Oxe2x80x94, or
an amino group with the formula 
xe2x80x83wherein R7 and R8 are the same or different and are H,or C1-C6 alkyl
(m) R9-hydroxylated-(C1-C6)alkylcarbonyl
(n) R9xe2x80x94(C1-C6)alkenylcarbonyl
X is
(a) NH, or
(b) O.
As used herein, the term xe2x80x9cC1-C6 alkylxe2x80x9d denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said C1-C6 alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
The term xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
The term xe2x80x9cpyridylxe2x80x9d includes the 2-, 3-, and 4-isomers and the terms thienyl and furanyl include the 2-, and 3-isomers.
Both the pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It should be understood that all the diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Also included in the invention are derivatives of the compounds of the Formula I which have the biological function of the compounds of the Formula I.
Depending on the process conditions the end products of the Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, preferably such acids are used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalogen acids such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbenzenesulphonic acid, toluenesulphonic acid or naphthalenesulphonic acid.
Preferred compounds according to the invention are those of Formula I wherein R1 is CH3 or CH2OH; R2 is CH3 or CH2CH3; R3 is CH3 or CH2CH3; R4 is H, Br, Cl or F; R5 is H or CH3.
Particularly preferred compounds according to the invention are:
8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine
8-(2-ethyl-6-methylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine
8-(2,6-dimethylbenzylamino)-3,6-dimethyl-2-hydroxymethylimidazo[1,2-a]pyridine
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl acetate
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl ethyl carbonate
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl N,N-dimethylcarbamate
1-[[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl]3-ethyl malonate
4-[[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methoxy]-4-oxobutanoic acid
4-[[8-(2-ethyl-6-methylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methoxy]-4-oxobutanoic acid
5-[[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methoxy]-5-oxopentanoic acid
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl 2-(dimethylamino)acetate
8-(2,6-dimethylbenzylamino)-2,3-dihydroxymethyl-imidazo[1,2-a]pyridine
The present invention also provides the following processes A and B for the manufacture of compounds with the general Formula I.
The process A for manufacture of compounds with the general Formula I comprises the following steps:
a) The imidazo[1,2-a]pyridine compounds of the Formula II 
wherein Y is a lower alkyl group, R represents H, CH3 or an ester group such as COOCH3, COOC2H5 etc, X1 is NH2 or OH and R5 is as defined for Formula I, can be prepared by reacting compounds of the general Formula III 
with compounds of the general Formula IV 
wherein Z is a leaving group such as halogen, mesyl, or tosyl.
The reaction is carried out under standard conditions in an inert solvent such as acetone acetonitrile, alcohol, N,N-dimethylformamide etc., with or without a base.
b) Compounds of the Formula II can be reacted with compounds of the Formula V 
wherein R2, R3 and R4 are as defined for Formula I and Z1 is a leaving group, such as halogen, tosyl or mesyl, under standard conditions in an inert solvent, with or without a base, to compounds of Formula VI 
wherein R2, R3, R4, R5 and X are as defined for Formula I, Y is a lower alkyl group and R is H, CH3 or an ester group such as COOCH3, COOC2H5 e.t.c.
c) Reduction of compounds of the general Formula VI e.g. by using lithium aluminium hydride or Red-Al(copyright) in ahn inert solvent such as tetrahydrofuran, ether or toluene yields the compounds of the general Formula I wherein R6 is H.
d) The substituent R6 of Formula I (R6xe2x89xa0H) can be introduced by standard acylating procedures carried out under standard conditions, eg. by reacting compounds of Formula I, wherein R6 is H, with the acid, acid halide or the anhydride of R6 (R6xe2x89xa0H) .
The process B for manufacture of compounds with the general Formula I comprises the following steps:
a) In compounds of Formula I wherein R6 is H, the hydroxymethyl group can be halogenated by standard methods in an inert solvent, to the corresponding halogenmethyl group of Formula VII 
b) The substituent R6 of Formula I (R6xe2x89xa0H) can be introduced by reacting compounds of Formula VII with the corresponding acid of R6 (R6xe2x89xa0H) . The reaction is carried out under standard conditions in an inert solvent with or without a base.
In a further aspect, the invention relates to compounds of the formula I for use in therapy, in particular for use against gastrointestinal inflammatory diseases. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.
The compounds according to the invention may thus be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance.
In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
The compounds of the invention can also be used in formulations together with other active ingredients, e.g. antibiotics such as amoxicillin.
For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets.
Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Hard gelatin capsules may contain granules of the active compound. Hard gelatin capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.1% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.
The compounds according to the invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving infection by Helicobacter pytori of human gastric mucosa. Such other active ingredients may be antimicrobial agents, in particular:
xcex2-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime;
macrolides such as erythromycin, or clarithromycin;
tetracyclines such as tetracycline or doxycycline;
aminoglycosides such as gentamycin, kanamycin or amikacin;
quinolones such as norfloxacin, ciprofloxacin or enoxacin;
others such as metronidazole, nitrofurantoin or chloramphenicol; or
preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.
The compounds according to the present invention can also be used together or in comibination for simultaneous, separate or sequential use with antacids such as aluminum hydroxide, magnesium carbonate and magnesium hydroxid or alginic acid, or together or in combination for simultaneous, separate or sequential use with pharmaceuticals which inhibit acid secretion, such as, H2-blockers (e.g cimetidine, ranitidine), H+/K+-ATPase inhibitors (e.g. omeprazole, pantoprazole, lansoprazole or rabeprazole), or together or in combination for simultaneous, separate or sequential use with gastroprokinetics (e.g. cisapride or mosapride).